The contact dissolution of cholesterol gallstones in human patients is a well recognized medical procedure and may be favored over surgical procedures to remove the gallstones in patients at increased risk for surgery; see, e.g., U.S. Pat. No. 4,205,086. The dissolution procedures normally involve infusion of the solvent into the biliary tract by means of a T-tube, nasobiliary tube, percutaneous transhepatic catheter or cholecystostomy tube by use of a constant infusion pump or by gravity or by manual repeated instillation and withdrawal using a syringe; see Palmer et al, Gut, 27, 2, 196 (1986). Frequently the stones fragment during the dissolution procedure, which advantageously increases the rate of dissolution.
A number of different types of solvents have been used or suggested for the dissolution procedure. These include organic solvents or liquids such as diethyl ether, chloroform or d-limonene as well as aqueous micellar solutions of bile salts. The aforementioned U.S. Pat. No. 4,205,086 also lists a large number of useful liquid fatty acids and the alcohol ethers thereof.
One solvent which has shown efficacy for dissolving cholesterol gallstones is monooctanoin, which is an esterified reaction product of glycerol and octanoic acid; see the aforementioned Gut article as well as Thistle et al, Gastroenterology, 78, 1016 (1980). Studies in vitro and in vivo have shown the ability of monooctanoin to significantly reduce and/or eliminate cholesterol gallstones by dissolving them so that the dissolved material can be eliminated or removed from the body. Monooctanoin has been marketed as an orphan drug with the approval of the Food and Drug Administration.
It is known that the viscosity characteristics of the solvent are important in the dissolution procedure [see Bogardus, J. Pharm. Sci, 73, 906 (1984)] since gallstones dissolve only very slowly in highly viscous solvents. Materials such as monooctanoin which are themselves of high viscosity may be diluted in order to be capable of being used in the standard perfusion equipment, such as by being dissolved or dispersed in varying amounts of water; see the aforementioned U.S. Pat. No. 4,205,086 and Gut article. While effective to reduce the viscosity of the monooctanoin somewhat (Bogardus, supra reports that addition of up to 15% water, the essential maximum, reduced the monooctanoin viscosity from 48 cp to about 28-30 cp), the water has no significant therapeutic effect in the gallstone dissolution treatment. Improvement in the dissolution efficacy obtained by dilution of the monooctanoin is slight.
The use of ethers to dissolve cholesterol gallstones is known. Two ethers which are of interest are diethyl ether (ethoxyethane) and methyl t-butyl ether (MTBE). The principal advantage of diethyl ether is that it is approved for some therapeutic uses with humans, being the common "ether" of anesthesia. In the past, however, it has not been possible to use diethyl ether for in vivo gallstone reduction because of its low boiling point (34.5.degree. C.) and high volatility. When instilled in the biliary tract, the liquid boils and the resultant ether vapor expands greatly in volume, leading to serious side effects of pain and nausea; Allen et al., Gastroenterology, 89, 5, 1097 (1985) ["Allen et al. (I)"]. MTBE also works well for dissolving gallstones in vitro and, in addition, has a satisfactory boiling point (55.degree. C.), but is not approved for therapeutic use; Allen et al., Gastroenterology, 88, 1, 122 (1985) ["Allen et al. (II)"].
Recently there has been developed a novel infusion pump which produces a high flow rate at low pressure. This pump has been described and claimed in U.S. patent application Ser. No. 06/871,775 (filed June 9, 1986) by applicant S. Zakko. While this pump has proved quite efficacious for gallstone dissolution, its satisfactory performance depends on being used with relatively low viscosity solvents. Consequently, monooctanoin by itself, or monooctanoin diluted with small amounts of water (Gut, supra) cannot be used in this type of pump because of its high viscosity. Similarly, there are other instances the high viscosity of monooctanoin prevents its practical use as a perfusion solvent.
It would therefore be advantageous to have a solvent composition which incorporates therapeutically effective amounts of monooctanoin and diethyl ether, which has a viscosity low enough to be used in all types of perfusion devices and which has a boiling point which permits its use in the body. Both principal components of the composition will thus contribute therapeutically to the dissolution of the gallstones.